11 alpha-hydroxy-4, 16-pregnadiene-3, 20-dione and esters



this invention will be apparent to one skilled United States Patent 11ot-HYDROXY-4,16-PREGNADIENE-3,20-DIONE AND ESTERS Douglas A. Lyttle and Robert H. Levin, Kalamazoo Township, Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Michigan No Drawing. Application August 27, 1953 Serial No. 37 6,989

16 Claims. (Cl. 260-39745) The present invention relates to novel steroid compounds and is more particularly concerned with Ila-oxygenated-4,16-pregnadiene-3,20-di0nes, especially with the novel l1u-hy.droxy-4,16-pregnadiene-3-20-dione and the Ila-esters thereof, and with a process for the production thereof.

The novel compounds of the present invention are illustratively represented by the following formula:

wherein R is hydrogen or the acyl radical of a carboxylic acid containing up to and including eight carbon atoms.

The novel compounds of this invention as well as the corresponding esters of other acids are prepared by forming a 3-hydrazone of an 11a-acyloxy-l7a-halo-4-prega nene-3,20-dione by treating l1a-acyloxy-4,l7ct-dihalopregnane-3,20-dione in the presence of an acid with an organic hydrazine capable of forming a hydrazone, hydrolyzing the 3-hydrazone, and dehydrohalogenating the resulting 11aacyloxy-17a-halo-4-pregnene-3,20-dione to form the desired 11ot-acyloxy-4,16=pregnadiene-3,20-dione which, when desired, can be hydrolyzed with acid or base to yield l1a-hydroxy-4,16-pregnadiene-3,20-dione. In this process any organic hydrazine containing two hydrogen atoms on one of the hydrazino nitrogen atoms can be used. The hydrolysis of the B-hydrazone group is advantageously effected by an exchange reaction with a ketaldone. The word ketaldone refers generically to aldehydes and ketones. For this purpose a ketaldone in which the 0x0 group is attached to an electrophylic group, as in pyruvic acid, pyruvic aldehyde, and benzaldehydes,

such as mcta-, para-, and ortho-hydroxybenzaldehydes, and meta-, para, and ortho-carboxy-benzaldehydes, is

advantageous. The dehydrohalogenation advantageously is effected with an amine such as pyridine. The hydrolysis is advantageously effected by means of a strong base such as sodium or potassium hydroxide.

It is an object of the present invention to provide the novel 1lot-hydroxyi,16-pregnadiene-3,20-dione and 11aacyloxy-4,l6-pregnadiene-3,ZO-diones. Another object of the invention is to provide a process for the production of lla-hydroxy-4,16-pregnadiene-3,20-dione and 11aacyloxy-4,16-pregnadiene-3,20-diones. Other objects of in the art to which this invention pertains. I

The novel compounds, 11a-hydroxy-4,16-pregnadiene-3, 20-dione and 11a-acyloxy-4,16-pregnadiene-3,ZO-dione, ar'e stable, easily crystallizable solids which have not only valuable pharmacological and physiological activity,

7 but are also important intermediates in the production of active ll-oxygenated keto steroids. For example, epoxidation of 11a-hydroxy-4,16-pregnadiene-3,20-diones or an ester thereof yields lla-hydroxy or 11a-acyloxy-16,17- oxidoprogesterone. The epoxide is then opened with hydrogen bromide and the resulting 16-bromo-l7a-hydroxy derivative is treated with zinc dust to remove the bromine and yield lla-hydroxyor 1la-acyloxy-17a-hydroxy- 'progesterone. Oxidation of 11u,17a-dihydroxyprogesterone or saponification and oxidation of lla-acyloxy-- l7ca-hYd1OXYPIOg6Si6lOI16 yields known 17u-hydroxy-11- lcetoprogesterone (21-desoxy E), which on treatment with lead tetraacetate, followed by saponification gives cortisone 1704,2l-dihydroxy-4-pregnene-3,11,20-trione) and on treatment with lithium aluminum hydride, with protection of the 3- and ZO-keto groups, gives 115,170:- dihydroxy-4-pregnene-3,ZO-dione (21-desoxy F), a new compound possessing pronounced inhibiting eifect on the secretion of the adrenocorticotropic hormone (ACTH) and having value, therefore, in the treatment of diseases where oversecretion of ACTH and adrenal hormones occurs, for example, in adrenal hyperplasia and pituitary basophilism (Cushings disease).

The starting compounds of the present invention are the 4,17ot-dihalo-1la-acyloxypregnane-3,ZO-diones. Advantageously, the acyl group is the carboxacyl group of a carboxylic acid containing not more than eight carbon atoms. The acyl group can be carboxacyl, sulfonacyl, phosphonacyl and the like and can have substituents, such as halo, mercapto, methoxy, ethoxy, hydroxy, carboxy, carbalkoxy, and the like. The halo group advantageously is bromine or chlorine. The starting compounds are prepared by treatment of 1lot-hydroxypregnane-3,20- dione or 1la-aCyloXypreguane-B,20-diones with an acid anhydride to form the corresponding enol esters, 3,1101, 20-triacyloxy-4,17(20)-pregnadienes, which by treatment with a hypohalous acid furnish the 4,17wdihalo-llaacyloxypregnane-3,20-dione as shown in Preparations 1 to 5, inclusive.

In carrying out the process of the present invention, the selected 4,17cz-dihalo-1lot-acyloxypregnane-I, ,20-dione is dissolved in an organic solvent, such as dioxane, acetic acid, acetone, dirnethylformamide, tertiary butyl alcohol, and ethanol, or mixtures of these solvents, with dioxane and acetic acid preferred, containing from five to 25 percent water, and to this solution is added, usually with continuous stirring, a solution of organic hydrazine, such as semicarbazide, phenylhydrazine, 2,4-dinitrophenylhydraziue, para-nitrophenylhydrazine, Otor fi-naphthyl semicarbazide, 2,4- and 3,5-dinitrophenylsemicarbazide, and other substituted hydrazines, with semicarbazide preferred.

The 1lot-acyloxy-l7a-halo-4-pregnene-3,ZO-dione 3-substituted hydrazone thus-obtained may be isolated from the mixture by adding more water and filtering the precipitated compound, or, in the preferred embodiment of the invention, may be immediately reacted in the solution with a suitable aldehyde or ketone without isolation.

The aldehydes or ketones used are usually pyruvic acid, j

' such as dioxane-water solution, while benzaldehydes are 1 .at room temperature, i. e., at about twenty to about thirty degrees centigrade between eight and 36 hours,

usually used in acetic acid solutions. The temperature of the reaction can vary between about zero and about Patented June 10, 1958 I and at temperatures, between fifty and seventy degrees centigrade, from one to about four hours. The product, l1a-acyloxy-l7a-halo-4-pregnene-3 ,20-dione, is isolated from the solution by pouring the cooled solution into water and extracting with a suitable solvent, such as dichloromethane, chloroform, ether or benzene, and evaporating the solvent from the resulting extract.

The 11a acyloxy-l7a-halo 4-pregnene-3,20 dione is then admixed with a large excess of an amine which acts both as a reactant and as a solvent, and the resulting solution is heated for a suitable length 05 time. Any suitable amine, such as, for example, pyridine, quinoline, picoline, lutidine, collidine, methylbenzylamine, aniline and the like can be used. Pyridine is the preferred amine. The reaction is generally conducted at the boiling point of the solution, but any temperature of about eighty to about 180 degrees centigrade is operative. The period of heating is usually dependent on the amine used, with the higher boiling amines requiring a shorter period of heating than the lower-boiling amines. Any period of about four to about 24 hours is operative, with about eight hours being preferred. If the amine used has a very high boiling point, a solvent such as benzene, toluene, xylene, or the like, can be advantageously employed for temperature control. The thus-produced lla-acyloxyl, 16-pregnadiene 3,20-dione is recovered from the reaction mixture'by conventional means, such as extraction and recrystallization.

In order to obtain 11a-hydroxy-4,l6-pregnadiene-3,20- dione, 1 1u-acyloxy-4, l 6-pregnadiene-3,20-dione, dissolved in an aqueous organic solvent, such as aqueous methanol, aqueous ethanol, aqueous dioxane, aqueous tertiary butyl alcohol, etc., is saponified with a base, such as sodium hydroxide, potassium hydroxide, barium hydroxide, or other like base, with sodium and potassium hydroxide preferred. The mixture is usually heated under reflux for a period of about two to about twelve hours, or even longer. The excess alkali then is neutralized suitably with a dilute mineral acid, such as hydrochloric or sulfuric acid, the organic solvent removed under reduced pressure, and the Water by azeotropic distillation with benzene. The remaining oil can be purified by conventional means such as, chromatography and recrystallization from suitable solvents such as acetone, Skellysolve B (hexanes) methanol, ethanol, ethyl acetate, and mixtures thereof.

The following examples illustrate the process and product of the present invention but are not to be construed as limiting.

PREPARATION 1 3,11 a,20-triacet0xy-3,17(20 -pregnadiene A mixture of 300 milligrams of llot-hydroxypregnane- 3,20-dione, fifteen milliliters of acetic anhydride and 140 milligrams of para-toluenesulfonic acid monohydrate was heated to boiling and allowed to distil slowly for four hours, most of the excess acetic anhydride being distilled at the end of this time interval. The last traces of excess acetic anhydride were removed under vacuum, and

I the resulting residue was cooled and dissolved in ether.

The ether solution was washed with cold ten percent aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the ether was distilled. The residue was dissolved in warm alcohol and allowed to crystallize.

The crystalline 3,1lot,20-triacetoxy-3,l7(20)-pregnadiene (150 milligrams) melted at 162167 degrees centigrade. Its structure was confirmed by infrared analysis.

PREPARATION 2 3,11u,20-tripropionoxy-3,l7(20)pregnadiene 4 PREPARATION 3 3,11 11,20-triheptanoyloxy-3J7(20) -pregnadiene 1la-hydroxypregnene-3,ZO-dione is converted by the procedure of Preparation 1 to 3,1la,2()-triheptanoyloxy 3,l7(20)-pregnadiene by heating for five hours with heptanoic anhydride and para-toluenesulfonic acid with toluene added as a solvent.

By the procedure of Preparations 1 through 3, other 3,lloc,20 triacyioxy-3,l7(20) pregnadienes prepared by heating l1ct-hydroxy-pregnane-3,ZO-dione with a selected acid anhydride include: 3,1lot,20-tributyroxy-3,l7(20)- pregnadiene, 3,11a,20-trivaleroxy-3,17()-pregnadiene, 3,11DC,20 triisovaleroxy-3,17(20) pregnadiene, 3,1 1a,20 trihexanoyloxy-3 l 7 20) -pregnadiene, 3,1 la,20-trioctanoyloxy-S 17(20) pregnadiene, 3,11a,20-tribenzoyloxy-3, l7(2C-)-pregnadiene, and the like.

PREPARATION 4 3,20-diacetoxy-11 ot-benzoyloxy-3J 7(20)-pregnadiene To 1lm-hydroxypregnane-3,ZO-dione was added an excess of benzoyl chloride. After the solution stood for one hour at room temperature, water was added and the crystals filtered off and washed. The thus-obtained llabenzoyloxypregnane-3,20-dione was then treated as in Preparation 1 with acetic anhydride to give 3,20-diacetoxy- Using the procedure of Preparation 1, lla-hydroxy- 1 1 a-bCIlZOYlOXY-3, 17 (20) -pregnadiene.

In the same manner as shown above by treating a selected lla-acyloxypregnane-3,20-dione with an acid anhydride, 3,20-enol esters of llot-acyloxypregnane-3,20- dione wherein the acyloxy group on the 3- and 20-position are equal and the Ila-position has another acyloxy group are obtained. Representative 3,11,20-triacyloxy3,l7- (20)-pregnadienes include: 3,20-dipropionoxy-1lot-benzoyloxy-3,17(20) -pregnadiene, 3,20-dibutyroxy-1lei-benzoyloxy-3,17 (20) -pregnadiene, 3,20-divaleroxy-1 la-benzoyloxy-3 l 7 20 -pregnadiene, 3 ,ZO-dihexanoyloxy-l lozbenzoyloxy-3,l7 (20) pregnadiene, 3,20 diacetoxy-l lapropionoxy-3,l7( 20) pregnadiene, 3,20 diacetoxy-llabutyroxy-3,l7(20 -pregnadiene, 3,20-diacetoxy-1lot-Valeroxy-3,l7 (20) pregnadiene, 3,20-diacetoxy lla-isovaleroxy-3 l 7 (20 -pregnadiene, 3 ,20-diacetoxy-1la-hexanoyloxy-3 17 (20) -pregnadiene, 3 ,ZO-diacetoxy-l la-heptanoyloxy-3,17 (20)-pregnadiene, 3,20-diacetoxy-1lu-octanoyloxy-3,17(20) pregnadiene, 3,20-diacetoxy Ila-phenylacetoxy-3 17 (20) pregnadiene, 3 ,20-diacetoxy-1la-toluyloxy-3,17(20 -pregnadiene, 3,20-diacetoxy-1la-(fl-cyclopentyl -propionoxy-3 l 7 20) -pregnadiene, 3,20-diacetoxyllot-trimethylacetoxy-3,17 (20) pregnadiene, 3,20-diacetoxy-l let-chloroacetoxy-3 l 7 20 pregnadiene, 3,20-diacetoxy-l l0. bromoacetoxy-3,l7(20) pregnadiene, 3,20-diacetoxy- 1 lrx-dichloroacetoxy-3, 17 (20) -pregnadiene, 3,20- diacetoxy-l la-trichloroacetoxy-3,17(2O -pregnadiene, 3, ZO-diacetoxy-1 1a-anisyloxy-3 l 7 2O -pregnadiene, 3 ,20-diacetoxyl lrt-galtylcxy-3,17(20) pregnadiene, 3,20-diacetoxy-l lot-mandelyloxy-3 l 7 20) -pregnadiene, 3 ,ZO-diacetoxy-l l a thioglycolyloxy-3,17(20) pregnadiene, 3,20-diaeetoXy-l la-toluenesulfonyloxy-il l 7 20 pregnadiene, 3 ZO-diacetoxy-l lot benzenesulfonyloxy 3,17(20)-pregnadiene, 3,20-diacetoxy 11m chlorobenzenesulfonyloxy-3, 17(20 pregnadiene, 3 ,ZO-diacetoxy-l 1a-( a-naphthylsulfonyloxy) -3 l 7 2Q pregnadiene, 3 ,ZO-diacetoxy-l lot-benzencphosphonyloxy-3, 17(20) -pregnadiene, and the like.

PREPARATION 5 4,1 7a-dibr0m0-1 1 a-acetoxypregnane-3,20-dione One hundred and fifty milligrams (150 milligrams) of '3,11a,20-triacetoxy-3,l7(20)-pregnadiene was dissolved in eight milliliters of tertiary butyl alcohol and treated with a solution of 128 milligrams of N-bromosuccinimide in fifteen milliliters of'tertiary butyl alcohol and with five milliliters of 0.8 Normal acid. After two hours of standing the solution was concentrated, diluted with water and the resulting crystals milligrams) collected. Four recrystallizations from alcohol gave white crystals of 110:.- acetoXy-4,17a-dibromopregnane 3,20-dione melting at 201 to 203 degrees centigrade with decomposition.

Analysis-Cale. for C H O Br: C, 51.89; H, 6.06; Br, 30.03. Found: C, 52.16; H, 5.96; Br, 30.01.

In the same manner, using 3,20-di-enol acylate of a selected llu-acyloxy pregnadiene compound and N- bromosuccinimide, the following compounds are prepared: 4,17a-dibromo-1 1a-propionyloxypregnane-3,20-dione, 4,17oc-dibIOIIlO 110a butyroxypregnane-S,20-dione,

4,17a-dibromo-11oa-valeroxypregnane-3,ZO-dione, 4,17udibromo-l 1a-isovaleroxypregnane-3,20-dione, 4,170z-dibromo-l 1u-hexanoyloxypregnane-3,20-dione, 4,1706-dibromo-l1u-heptanoyloxypregnane-3,20-dione, 4,17oc-dibromo-l la-octanoyloxypregnane 3,20 dione, 4,17oc-dibromo-l la-benzoyloxypregnane-3,ZO-dione, 4,17oc-dib10- mo-l1a-phenylacetoXypregnane-3,20-dione, 4,17a-dib10- mo-l 1 a-toluyloxypregnane-3,20-dione, 4,17a-dibromo- 11 x-(;3 cyclopentyl) propionoxypregnane 3,20 dione,

' 4,170c-dlbI'0IHO-11o: trimethylacetoXypregnane-3,20-dione,

4,17u-dibromo-1lot-chloroacetoxypregnane 3,20 dione, 4,17a-dlbIOIn-11ot dichloroacetoxypregnane-3,20-dione, 4,17a-dibromo-l1u trichloroacetoxypregnane-3,20-dione, 4,17a-dibromo 11a bromoacetoXypregnane-3,20-dione, 4,17a-dibromo-1 la-anisyloxypregnane-3,20-dione, 4,17ocdibromo-l1m-gallyloXypregnane-3,20-dione, 4,17a-dibromo-l1a-mandelyloxypregnane-3,20-dione, 4,17u-dibromo- 11a-thioglycolyloxypregnane-3,20-dione, 4,17a-dibromo- 1lm-toluenesulfonyloxypregnane-3,ZO-dione, 4,17a-dibromo-l1a-benzenesulfonyloxypregnane-3,20-dione, 4,1711- dibromo 11a chlorobenzenesulfonyloxypregnane-3,20- dione, 4,170c-dib1'OI11O-1 1a-(a-naphthylsulfonyloxy)-pregnane3,20-dione, 4,l7adibromo-1la-benzenephosphonyloXypregnane-3,20-dione, and the like.

PREPARATION 6 4,1 7u-dichlor0-11 a-acetoxypregntzne-iZO-dione Following the procedure given in Preparation 5, but using hypochlorous acid, or a mineral acid with a hypochlorite such as sodium or calcium hypochlorite, or N- chlorosuccinimide or N-chloroacetamide with dilute sulfuric acid instead of the N-bromosuccinimide, to treat a solution of 3,1la,20-triacetoxy-3,l7(20)-pregnadiene in tertiary butyl alcohol, 4,17a-dichloro-1la-acetoxypregnane-3,20-dione is obtained.

In the same manner, using 3,20-di-enol acylates of the selected ,lla-acyloxypregnane compound and hypochlorousacid or an N-chloroacylamide, the following compounds are prepared: 4,l7ot-dichloro-1la-propionoxypregnane-3,20-dione, 4,17u-dichloro-1 lot-butyroxypregnane-3,20-dione, 4,17a-diChlOIO-1 let-valeroxypregnane- 3,20-dione, 4,170c-diChlOlO-1 1a-isovaleroxypregnane-il,20- dione, 4,17u-dichloro-1lu-hexanoyloxypregnane-3,20-dione, 4,17a-dichloro-11a-heptanoyloxypregnane-3,20-dione, 4,17a-dichloro-llu-octanoyloxypregnane-3,20-dione, 4,17u-dichloro-1 1 a-benzoXylpregnane-3,20-dione, 4,170;- dic hloro-lla-phenylacetoxypregnane-3,20-dione, 4,170;- dichloro-l 1a-t0luyloXypregnane-3,20-dione, 4,17oc-dichl0- ro-l 1oc-( B-cyclopentyl)-propionoxypregnane 3,20 dione, 4,17u-dichloro-l1e-trimethylacetoxypregnane-3,20 dione, 4,17u-dichloro-1lqg-chloroacetoxypregnane 3,20 dione, 4,17oc-diChlOI'O-1 la-dichloroacetoxypregnane 3,20-dione, 4,17a-dichloro-1l'a-bromoacetoxypregnane 3,20 dione, 4,17a-dichloro-l1u-anisyloxypregnane-3,20-dione, 4,170;- dichloro-l 1u-gallyloxypregnane-3,20-dione, 4,17cc-diChlO- ro-1 1u-mandelyloxypregnane-3,20-dione, 4,17a-dichloro- 11a-thioglycolyloxypregnane-3,20-dione, 4,17a-dichloro- 1 1a-toluenesulfonyloxypregnane-3,20-dione, 4,17a-dichloro-lla-benzenesulfonyloxypregnane-3,20-dione, 4,17cc-dichloro 1'10: chlorobenzenesulfonyloXypregnane-3,20-dione, 4,17oz-diChl01O-1 lua-naphthylsulfonyloxy) -pregmane-3,20-dione, 4,17a-dichloro-1la-benzenephosphonyloXypregnane-3,20-dione, and the like.

Found: Br, 17.65.

EXAMPLE 1 I1ot-acetoxy-l7a-br0m0-4-pregnene-3,20-dione liter of pyruvic acid in five milliliters of water was added.

The reaction mixture was then heated to about seventy degrees centigrade for a period of three hours, thereafter cooled and poured into 200 milliliters of water. The thus-produced 1la-acetoxy-17u-brorno-4-pregnene-3,20- dione was extracted from the aqueous mixture with three 75-milliliter portions of methylene dichloride. The extracts were washed with two fifty-milliliter portions of one percent aqueous sodium hydroxide solution, then with Water until the wash-Water was neutral, and then dried over anhydrous sodium sulfate and concentrated to yield 0.452 gram of an oil. This oil, containing acetoxy-17a-bromo-4-pregnene-3,20-dione was purified by chromatography and recrystallization from acetone and Skellysolve B (hexanes) yielding 162 milligrams of 11aacetoxy-l7a-brorno 4 pregnane-3,20-dione of melting point 166 to 168 degrees centigrade.

Analysis.Calculated for C H BrO Br, 17.70.

EXAMPLE 2 A 11 a-propionoxy-l 7u-chloro-4-pregnene-3,20-dione In a manner as given in Example 1, 4,17a-dichloro 11u-propionoxypregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield 11apropionoxy-17a-chloro-4-pregnane-3,20-dione.

EXAMPLE 3 11 a-butyroxy-J 7u-chl0r0-4-pregnene-3,20-diorte In a manner as given in Example 1, 4,17oc-diChlO1O-11ocbutyroXypregnane-3,20-dione is dehydrohalogenated with semicarbazide and pyruvic acid to yield llot-butyroxy- 17a-chloro-4-pregnene-3,20-dione.

EXAMPLE 5 11 u-benzoyloxy-J 7a-br0mo-4-pregnene-3,20-dione In a manner as given in Example 1, 4,17oc-dib1Om0-11ubenzoyloxypregnane-3,20-dione is dehydrohalogenated with sernicarbazide and pyruvic acid to yield llu-benzoyloxy-17a-bromo-4-pregnene-3,20-dione.

Following the procedure of Examples 1 through 5 using any of .the various preparations under Preparations 5 and 6, there are obtained the following 11a-acyloX'y-17ahalo 4 pregnene 3,20 diones: 11a-valeroxy-l7achloroor brom-o-4-pregnene-3,ZO-dione, lla-isovaleroxyl7a-chloro or bromo 4 pregnene 3,20 dione, 11ahexanoyloxy 17m chloroor brom'0-4-pregnene-3,20- dione, 11a heptanoyloxy 170a chloroor bromo-4- pregnene-3,20-dione, lla-octanoyloxy 17a chloro- 0r bromo 4 pregnene 3,20 dione, llu-phenyla-cetoxy- 17a-chlor0- or bromo 4 pregnene 3,20 dione, 11atoluyloxy-l7u-chloroor bromo-4-pregnene-3,20-dione, 11a-trimethylacetoxy-l7a-chloroor bromo-4-pregnene- 7 3,20-dione, lla-chloroacetoxy 17cc chloroor bromo- 4-pregnene-3,20-dione, 11cc dichloroacetoxy-17a-chloroor br-omo 4 pregnene 3,20 dione, lla-trichloroacetoxy 170: chloroor bromo-4-pregnene-3,20-dione, llix-bromoacetoxy 17oz chloroor bromo-4-pregnene- 3,20-dione, 11o: anisyloxy 17a chloroor bionic-4- pregnene-3,20-dione, 11a gmlyloxy 17a chloroor bromo 4 pregnene 3,20 dione, 11o; mandelyloxy- 17a-chloroor .bromo-4-pregnene 3,20 dio-ne, 11w thioglycolyloxy 17a chloroor brom'o 4 pregnene- 3,20-dione, 1lu-toluenesulfonyloxy-l7a-chicroor brainc- 4-pregnene 3,20 dione, 11cc bEHZCHESUiIODYI-GXY-17o;- chloroor bromo 4 pregnene-3,20-dione, lla-chlorobenzenesulfonyloxy 17a chloroor bromo-4-pregnene- 3,20-dione, 11o;-(tx-naphthylsulfonyloxyy17zx-chloroor bromo 4 pregnene 3,20 dione, lla-benzenephosphonyloxy-17a-chloro or bremo-4-pregnene-3,ZO-dione, and the like.

EXAMPLE 6 11a-acetoxy-4Jd-pregnadiene-3,20-di0ne One gram of llot-acetoxy-l7a-bromo-4-pregnene-3,20- dione was dissolved in 25 milliliters of dry pyridine and heated under reflux during a period of 24 hours. Thereafter most of the pyridine was removed by distillation under reduced pressure. The residue was then dissolved in fifty milliliters of benzene. Fifty milliliters of water were added to the benzene solution and the mixture was washed with one Normal hydrochloric acid until all pyridine was removed. Thereafter the benzene solution was washed With'water until neutral, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residual oil crystallized spontaneously. The thus-obtained crystals of llaacetoxy-4,16-pregnadiene-3,20-dione were recrystallized from a solution consisting of two milliliters of ethyl acetate and twenty milliliters of Skellysolve B (hexanes) yielding 708- milligrams (86.3 percent) of ll'u-acetoxy- 4,l6-pregnadiene 3,20-dione in the form of needles. A second recrystallization from 2.5 milliliters of isopropyl alcohol yielded 622 milligrams (75.7 percent) of 11aacetoxy-4,16-pregnadiene-3,20-dine of melting point 176 to 178 degrees centigrade.

EXAMPLE 7 1'1a-hydroxy-4J6-pregnadiene-3,20-a'i0ne A mixture of 740 milligrams (two millimoles) of 110cacetoxy-4,16-pregnadiene-3,20-dione, 168 milligrams of potassium hydroxide, seven milliliters of Water and twenty milliliters of purified dioxane was heated under reflux for a period of seven hours. The excess alkali was then neutralized with one tenth Normal hydrochloric acid, and some silica which separated, was removed by filtration. The volatile solvents were removed by distillation under reduced presure and the last traces of water by azeotropic distillation with benzene. The remainder, an oil which could not be induced to crystallize, was chromatographed over 65 grams of Florisil (anhydrous magnesium'silicate). Practically all the material was recovered with a solution containing one part of acetone and nine parts of Skellysolve B (hexanes). The like fractions were combined, concentrated and the residue recrystallized from a solution consisting of fifteen milliliters of ethyl acetate and twenty milliliters of Skellysolve B (hexanes) yielding 447 milligrams (68 percent) of llot-hydroxy- 4,16-pregnadiene-3,20-dione of melting point 179 to 180 degrees Centigrade.

Analysis.-Calculated for C H O C, 76.79; H, 8.59. Found: 76.92; H, 8.39.

EXAMPLE 8 11a-benzoyloxy-l7e-br0m0-4-pregnene-3,ZO-dione A solution of 4,17a-dibrom0-lla-benzoyloxypregnane- 3,20-dione dissolved in acetic acid, was admixed with a solution of 2,4-dinitrophenylhydrazine hydrochloride and sodium acetate in acetic acid. After stirring for eighteen,

hours at room temperature the mixture was poured into water and the 3-(2,4-din.itrophenyl)-hydrazone of 11a: benzoyloxy 170a bromo-4-pregnene-3,20-dione was obtained by extraction with methylene dichloride. The thusobtained 2,4-dinitrophenylhydrazone was then heated with para-hydroxybenzaldehyde in acetic acid solution to give 1loc-bfil'lZOYlOXY-17oc-bIOII10-4-1JIt-3gDCHG-3,ZO-diOIlc.

In the same manner as in the above example but using 3,5-dinitrophenylhydrazone, phenylhydrazine, para-nitrophenylhydrazlne, semicarbazide, or 01- or B-naphthylsemicarbazide instead of 2,4-dinitrophenylhydrazine and pyruvic acid, pyruvic aldehyde or carboxybenzaldehydes instead of para hydroxybenzaldehyde to treat llabenzoyloxy 4,17zz dibromopregnane-3,20-dione, 11ozbensoyloxy-l7a-bromo-4-pregnene-3,ZO-dione is obtained.

EXAMPLE 9 11oc-benzoy[way-4,16-pregnadiene-3,ZO-dione A solution of llu-benzoyloxy-l7a-bromo-4-pregnene- 3,20-dione, dissolved in collidine, was kept during a period of 24 hours at a temperature between about and degrees Centigrade. Thereafter the reaction mixture was diluted with ether and washed repeatedly with one Normal hydrochloric acid to remove the collidine. The excess acid was removed from the ether solution by washing with a sodium carbonate solution and finally water. The ether solution was then dried over anhydrous sodium sulfate and evaporated. The thus-obtained residue was chromatographed as described in Example 2 to yield 1la-benzoyloxy-4,16-pregnadiene-3,ZO-di-one.

EXAMPLE 10 1 1 a-hydroxy-4,16-pregnadiene-3,20-di0ne In a manner as given in Example 7, lla-benzolyoxy- 4,l6-pregnadiene-3,20-dione is hydralyzed with potassium hydroxide in aqueous dioxane to give lla-hydroxy-4,16- pregnadiene-3,20-dione.

EXAMPLE 1 1 v '11oc-pr0pion0xy-4,l6-pregnadiene-3,20-di0ne In a manner as given in Example 6, llu-propionoxy- 17a-chloroA-pregnene-3,20-dione is dehydrohalogenated with pyridine to yield 1la-propionoxy-4,16-pregnadiene- 3,20-dione.

EXAMPLE 12 11 a-hydro'xy-4,16-pregnadiene-3,20-dione In a manner as given in Example 7, lla-propionoxy- 4,16-pregnadiene-3,20-dione is hydrolyzed with sodium hydroxide in tertiary butyl alcohol to give lla-hydroxy- 4,16-pregnadiene-3,20-di0ne.

EXAMPLE 13 11a-(fi-cyclopentylpropionoxy) -4,16-pr'egnadiene- 3,20-di0ne In a manner as given in Example 6, llot-(p-cyclopentylpropionoxy)-l7ot-chloro-4-pregnene-3,20-dione is dehydrohalogenated with pyridine to yield lla-(B-cyclopentylpropionoxy)-4,16-pregnadiene-3,20-dione.

' EXAMPLE 14 11a-hydr0xy-4J6-pregnadiene-3,20-di0ne In a manner as given in Example 7, lloc-(fi-CYCIO- pentylpropionoxy) 4,16 pregnadiene-3,20-dione is hydrolyzed with potassium hydroxide in aqueous dioxane to give 11a-hydroxy-4,16-pregnadiene-3,20-dione.

EXAMPLE 15 11a-butyroxy-4J6-pregnadiene-3,ZO-dione In a manner as given in Example 6, lla-butyroxyl7a-chloro-4-pregnene-3,20-dione is dehydrohalogenated with pyridine to yield 1la-butyroxy-4,l6-pregnadiene- 3,20-dione.

EXAMPLE 16 11 u-hydrxy-4,16-pregnadiene-3,20-di0ne In a manner as given in Example 7, lla-butyroxy- 4,16-pregnadiene-3,20-dione is hydrolyzed with potas sium hydroxide in aqueous dioxane to give lla-hYdI'OXY- 4,16-pregnadiene-3,20-dione.

- EXAMPLE 17 11a-hydr0xy-4J6-pregnadiene-3,20-dione In a manner as given in Example 7, lla-benzoyloxy- 4,16-pregnadiene-3,20 dione is hydrolyzed with potassium hydroxide in aqueous dioxane to give 11ot-hydroxy-4,16- pregnadiene-3,20-dione.

In the same manner as in Examples, 6, 9, 11, 13 and 15, selected 11tat-acyloxy-17u-halo-4-pregnene-3,20-diones are heated with pyridine, collidine, lutidine, picoline, or other bases to produce the corresponding lla-acyloxy- 4,l6-pregnadiene-3,20-diones such as: 11a-valeroxy-4,16- pregnadiene 3,20 dione, 11a-isovaleroxy-4,16-pregnadiene-3,20-dione, 11a-hexanoyloxy-4,16-pregnadiene-3,20- dione, 11u-heptanoyloxy-4,16-pregnadiene -3,20 dione, 11a-octanoyloxy-4,16 pregnadiene 3,20 dione, 11aphenylacetoxy-4,16-pregnadiene 3,20 dione, 11a-toluy1oxy-4,16-pregnadiene-3,20-dione, 11a trimethylacetoxy-4,16-pregnadiene-3,20-dione, 11a-mono-, di-, and trichloroacetoxy-4,16-pregnadiene 3,20 dione, 11abromoacetoxy-4,16 pregnadiene 3,20 dione, 11aanisyloxy-4,16-pregnadiene 3,20 dione, lla-gallyloxy- 4,16-pregnadiene 3,20 dione, 11a-mandelyloxy-4,l6- pregnadiene-3,20-dione, 1la-thioglycolyloxy-4,l6-pregnadiene 3,20 dione, 1la-toluenesulfony1oxy-4,l6-pregnadiene-3,20-dione, 11a benzenesulfonyloxy-4,16-pregnadiene-3,20-dione, 110a chlorobenzenesulfonyloxy-4,l6- pregnadiene-3,20-dione, 11ot-(at-naphthylsulfonyloxy)-4,16-

pregnadiene-3,20-dione, 11a-benzenephosphonyloxy-4,16- pregnadiene-3,20-dione, and the like.

In the same manner as in Examples 7, 10, 12, 14, 16 and 17, a thus-obtained 11a-acyloxy-4,16-pregnadiene- 3,20-dione upon heating with sodium or potassium hydroxide in aqueous dioxane, methanol, ethanol, or tertiary butyl alcohol yields 11a-hydroxy-4,16-pregnadiene-3,20- dione.

It is to be understood that the invention is not to be limited to the exact details or exact compounds shown and described, as obvious modifications and equivalents Will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. An 11a-oxygenated-4,16-pregnadiene-3,20-dione of the formula:

OHs

8. A process for the production of a compound se lected from the group consisting of 11a-hydroxy-4,16- pregnadiene-3,20-dione' and esters thereof which compr1se: forming a 3-hydrazone of 11a-acyloxy-l7u-halo- 4-pregnene-3,20-dione by reacting a 4,17ot-dihfllO-11uacyloxypregnane-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced S-hydrazone by an exchange reaction with a ketaldone to yield the corresponding 11a-acyloxy-17a-halo-4-pregnene- 3,20-dione, and dehydrohalogenating the thus-obtained llot-acyloxy-l7a-halo-4-pregnene-3,20-dione to obtain the corresponding 1 laacyloxy-4, l 6-pregnadiene-3,20-dione.

. 9. A process 'for the production of a compound selected from the group consisting of 11vt-hydroxy-4,l6- pregnadiene-3,20-dione and esters thereof which comprise: forming a 3-hydrazone of 11a-acyloxy-l7a-halo- 4-preg-nene-3,20-dione by reacting a 4,17oc-dihfilO-11ocacyloxypregnane-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone selected from the group of pyruvic acid, pyruvic alde hyde, and benzaldehydes to yield the cor-responding 11aacyloxy-17ot-halo-4-pregnene 3,20-dione, and dehydrohalogenating the thus-obtained 11a-acy1oxy-17u-halo-4- pregnene-3,20-dione to obtain the corresponding 11aacyloxy-4,l6-pregnadiene-3,20-dione.

10. A process for the production of 11a-acyloxy-4,l6- pregnadiene-3,20-dione which comprise: forming the 3- hydrazone of l1a-acyloxy-l7a-chloro-4-pregnene- 3,20- dione by reacting a 4,17ot-dichloro-1la-acyloxypregnane- 3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone selected from the group of pyruvic acid, pyruvic aldehyde, and benzaldehydes, to yield the corresponding lla-acyloxy-lh-chloro- 4-pregnene-3,20-dione, and heating the thus obtained cacyloxy-17a-chloro-4-pregnene-3,20-dione with an amine to obtain the corresponding 11u-acyloxy-4,16-pregnadiene- 3,20-dione.

11. A process for the production of 11a-acyloxy-4,16- pregnadiene-3,20-dione which comprise: forming the 3- hydrazone of 1l t-acyloxy-l7u-chloro-4-pregnene- 3,20- dione by reacting a 4,17oc-dichloro-1lot-acyloxypregnane- 3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone to yield the corresponding 1106 acyloxy-17a-ch1oro 4 pregnene-3,20- dione, and heating the thus obtained 11a-acyloxy-17achloro-4-pregnene-3,20-dione with an amine selected from the group consisting of pyridine, collidine, picoline, lutidine and aniline to obtain the corresponding Ila-acyloxy- 4,16-pregnadiene-3,20-dione.

12. A process for the production of 11a-acyloxy-4,16- pregnadiene-3,20-dione which comprise: reacting a 4,170:- dichloro-llat-acyloxypregnane 3,20 dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide, treating the thus obtained 3-semicarbazone of l1a-acyloxy-l7a-chloro-4-pregnene- 3,20-dione with pyruvic acid to obtain the corresponding 1lu-acyloxy-17a-chloro-4-pregnene-3,20-dione, and heat,- ing the thus obtained lla-acyloxy-17a-chloro-4-pregnene- 3,20-dione with pyridine to obtain the corresponding 11aacyloxy-4,16-pregnadiene-3,20-dione.

13. In a process for the production of lla-hydroxy- 4,16-pregnadiene-3,ZO-dione, the steps which comprise: forming the 3-hydrazone of 11a-acyloxy-17whalo-4- pregnene-3,20-dione by reacting a 4,17a-dihalo-11a-acyloxypregnene-3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone selected from the group of pyruvic acid, pyruvic aldehyde, and benzaldehydes to yield the corresponding lla-acyloxy- 17a-halo-4-pregnene-3,20-dione, heating the thus obtained 11a acyloxy 17oz halo 4-pregnene-3,20-dione with an amine to obtain the corresponding 1la-acyloXy-4,16- pregnadiene-3,20-dione, and hydrolyzing the thus-obtained Ila-ester to 11a-hydroxy-4,l6-pregnadiene-3,ZO-dione.

14. A process for the production of 11u-acy1oXy-4,16- pregnadiene-3,20-dione Which comprise: forming the 3- hydrazone of llot-acyloxy-l7a-bromo-4-pregnene-3,20-dione by reacting a 4,l7a-dibrorno-llot-acyloxypregnane- 3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, With an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone selected from the group of pyruvic acid, pyruvic aldehyde, and benzaldehydes, to yield the corresponding 1la-acyloxy-17ot-bromo- 4-pregnene-3,20-dione, and heating the thus-obtained 11aacyloxy-l7a-bromo-4-pregnene-3,20-dione with an amine to obtain the corresponding 1lot-acyloxy-4,l'6-pregna diene-3,20-dione.

15. A process for the production of 11a-acyloxy-4,l6- pregnadiene-3,20-dione which comprise: forming the 3- hydrazone of 11a-acyloxy-17a-bromo-4-pregnene-3,20-di- 7 one by reacting a 4,17wdibr0n1o-1lot-acyloxypregnane- 3,20-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with an organic hydrazine, hydrolyzing the thus-produced 3-hydrazone by an exchange reaction with a ketaldone to yield the corresponding llot-acyloxy-17wbrorno-4pregnene-3,20-dione, and heating the thus obtained 11a-acyloXy-l7u-bromo- 4-pregnene-3,20-dione With an amine selected from the group consisting of pyridine, collidine, picoline, lutidine and aniline to obtain the corresponding 11x-acyloXy-4,16- pregnadiene-3,20-dione.

16. A process for the production of 11a-acyloXy-4,l6- pregnadiene-3,20-dione which comprise: reacting a 4,170:- dibromo-l1ot-acyloxy-pregnane-3,ZO-dione, wherein the acyloxy group contains from one to eight carbon atoms, inclusive, with semicarbazide, treating the thus obtained 3-semicarbazone of 11u-acyloxy-17ot-bromo-4-pregnene- 3,20-dione with pyruvic acid to obtain the corresponding llot-acyloxy-17wbron1o-4-pregnene-3,ZO-dione, and heating the thus obtained 11a-acyloxy-17u-bromo-4-pregnene- 3,20-dione with pyridine to obtain the corresponding llaacyloxy-4,l6-pregnadiene-3,20-dione.

No references cited. 

1. AN 11A-OXYGENATED-4,16-PREGNADIENE-3,20-DIONE OF THE FORMULA: 